State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
Department of Surgical Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China.
Oncogene. 2018 Feb 8;37(6):768-776. doi: 10.1038/onc.2017.370. Epub 2017 Oct 23.
Epithelial-mesenchymal transition (EMT) is a process during which normal epithelial cells acquire mesenchymal characteristics. EMT has a critical role in various human diseases especially in cancer. EMT facilitates tumor initiation and progression by mediating cancer cell stemness and motility. Zinc finger transcription factor SNAIL is one of the most important initiators of EMT. Therefore, it is of great significance to understand the regulating mechanism of SNAIL. In this study, we carried out a luciferase-based genome-wide screening using small interfering RNA library against ~200 of E3 ligases and ubiquitin-related genes and identified SOCS box protein SPSB3 as a novel E3 ligase component that targets SNAIL into polyubiquitination and degradation in response to GSK-3β phosphorylation of SNAIL. Functionally, we observed that SPSB3 overexpression greatly inhibits tumor metastasis by regulating SNAIL degradation both in vitro and in vivo. The expression of SPSB3 and SNAIL are negatively correlated in human esophageal squamous cell carcinoma tissues, and low SPSB3 expression indicates lymph node metastasis. Moreover, high SPSB3 expression indicates good survivals in various kinds of cancer. Collectively, these findings suggest that SPSB3-mediated SNAIL degradation has a vital role in regulating EMT and cancer progression.
上皮-间充质转化（EMT）是正常上皮细胞获得间充质特征的过程。EMT 在各种人类疾病中特别是癌症中具有关键作用。EMT 通过介导癌细胞干性和运动性促进肿瘤起始和进展。锌指转录因子 SNAIL 是 EMT 的最重要启动子之一。因此，了解 SNAIL 的调节机制具有重要意义。在这项研究中，我们使用针对~200 个 E3 连接酶和泛素相关基因的小干扰 RNA 文库进行了基于荧光素酶的全基因组筛选，鉴定出 SOCS 盒蛋白 SPSB3 是一种新型 E3 连接酶成分，可将 SNAIL 靶向多泛素化和降解，以响应 SNAIL 的 GSK-3β 磷酸化。功能上，我们观察到 SPSB3 过表达通过调节 SNAIL 降解，在体外和体内都能极大地抑制肿瘤转移。人食管鳞状细胞癌组织中 SPSB3 和 SNAIL 的表达呈负相关，SPSB3 低表达预示着淋巴结转移。此外，SPSB3 高表达表明在各种癌症中具有良好的存活率。总之，这些发现表明 SPSB3 介导的 SNAIL 降解在调节 EMT 和癌症进展中具有重要作用。
